1,2,4-oxadiazole compounds as inhibitors of CD47 signalling pathways
The present invention relates to compounds of formula (I), compositions, methods and uses involving the said formula (I) that inhibit CD47 signaling pathway. The present invention also relates to methods of making such compounds and their uses for the treatment of diseases or disorders mediated by CD47.
1 . A method of modulating macrophage phagocytic activity towards a cancer cell or tumor cell in an individual comprising administering to said individual an effective amount of a compound of formula (I):
or a pharmaceutically acceptable salt or an amide or an ester, or a stereoisomer thereof;
wherein,
R a is hydrogen or acyl; and R 1 represents hydrogen, —(CH 2 ) 2 CONH 2 , —(CH 2 ) 2 COOH, —CH 2 COOH, —(CH 2 ) 3 NHC(═NH)NH 2 , —(CH 2 ) 4 NH 2 , —CH 2 CONH 2 , —CH(CH 3 )—CH 2 —CH 3 , —CH 2 -aryl, or —CH 2 -heteroaryl; wherein the said aryl and heteroaryl are unsubstituted; or R a and R 1 together with the atoms to which they are attached form pyrrolidine ring optionally substituted with oxo group;
R 2 represents hydrogen, —CH 2 —OH, —(CH 2 ) 3 NHC(═NH)NH 2 , —(CH 2 ) 2 CONH 2 , —(CH 2 ) 2 COOH, —CH 2 -aryl, or —CH 2 -heteroaryl; wherein the said aryl and heteroaryl are unsubstituted;
R b is hydrogen; and R 3 represents hydrogen, —CH 2 -aryl, —(CH 2 ) 3 NHC(═NH)NH 2 , —CH 2 COOH, —CH(CH 3 )—CH 2 —CH 3 , —CH 2 —CH(CH 3 ) 2 , —(CH 2 ) 2 CONH 2 , —(CH 2 ) 2 COOH, —(CH 2 ) 4 NH 2 or —CH 2 -heteroaryl; wherein the said aryl and heteroaryl are unsubstituted; or R b and R 3 , together with the atoms to which they are attached form pyrrolidine ring.
2 . The method of claim 1 , wherein R 1 represents hydrogen, —(CH 2 ) 2 CONH 2 , —(CH 2 ) 2 COOH, —(CH 2 ) 3 NHC(═NH)NH 2 , —(CH 2 ) 4 NH 2 , —CH 2 CONH 2 , —CH(CH 3 )—CH 2 —CH 3 , —CH 2 -phenyl, —CH 2 -indolyl, or —CH 2 -imidazolyl.
3 . The method of claim 1 , wherein R 2 represents hydrogen, —CH 2 —OH, —(CH 2 ) 3 NHC(═NH)NH 2 , —(CH 2 ) 2 CONH 2 , —(CH 2 ) 2 COOH, —CH 2 -phenyl, —CH 2 -indolyl, or —CH 2 -imidazolyl.
4 . The method of claim 1 , wherein R 3 represents hydrogen, —(CH 2 ) 3 NHC(═NH)NH 2 , —CH 2 COOH, —CH(CH 3 )—CH 2 —CH 3 , —CH 2 —CH(CH 3 ) 2 , —(CH 2 ) 2 CONH 2 , —(CH 2 ) 2 COOH, —(CH 2 ) 4 NH 2 , —CH 2 -phenyl, —CH 2 -indolyl, or —CH 2 -imidazolyl.
5 . The method of claim 1 , wherein the compound is represented by compound of formula (IA):
or a pharmaceutically acceptable salt or an amide or an ester, or a stereoisomer thereof; wherein, R 1 R a and R 2 are as defined in claim 1 .
6 . The method of claim 5 , wherein R 1 represents hydrogen, —CH 2 —COOH, —CH 2 —CONH 2 , —CH(CH 3 )—CH 2 —CH 3 , —(CH 2 ) 2 CONH 2 , —(CH 2 ) 2 COOH, —(CH 2 ) 3 NHC(═NH)NH 2 , —(CH 2 ) 4 NH 2 , —CH 2 -phenyl, —CH 2 -indolyl or —CH 2 -imidazolyl.
7 . The method of claim 5 , wherein R 2 represents hydrogen, —CH 2 —OH, —(CH 2 ) 3 NHC(═NH)NH 2 , —(CH 2 ) 2 CONH 2 , —(CH 2 ) 2 COOH, —CH 2 -phenyl, or —CH 2 -imidazolyl.
8 . The method of claim 5 , wherein,
R a is hydrogen; and R 1 represents hydrogen, —CH 2 —COOH, —CH 2 —CONH 2 , —CH(CH 3 )—CH 2 —CH 3 , —(CH 2 ) 2 CONH 2 , —(CH 2 ) 2 COOH, —(CH 2 ) 3 NHC(═NH)NH 2 , —(CH 2 ) 4 NH 2 , —CH 2 -phenyl, —CH 2 -indolyl or —CH 2 -imidazolyl; and
R 2 represents hydrogen, —CH 2 —OH, —(CH 2 ) 2 CONH 2 , —(CH 2 ) 3 NHC(═NH)NH 2 , —(CH 2 ) 2 COOH or —CH 2 -phenyl.
9 . The method of claim 1 , wherein the compound is represented by compound of formula (IB):
or a pharmaceutically acceptable salt or an amide or an ester, or a stereoisomer thereof; wherein, R 1 , R a , R b and R 3 are as defined in claim 1 .
10 . The method of claim 9 , wherein, R 1 represents hydrogen, —CH 2 —COOH, —CH 2 —CONH 2 , —CH(CH 3 )—CH 2 —CH 3 , —(CH 2 ) 2 CONH 2 , —(CH 2 ) 2 COOH, —(CH 2 ) 3 NHC(═NH)NH 2 , —(CH 2 ) 4 NH 2 , —CH 2 -indolyl, —CH 2 -imidazolyl or —CH 2 -phenyl.
11 . The method of claim 9 wherein, R b is hydrogen; R 3 represents hydrogen, —CH 2 —COOH, —CH 2 —CH(CH 3 ) 2 , —CH(CH 3 )—CH 2 —CH 3 , —(CH 2 ) 4 NH 2 , —(CH 2 ) 2 CONH 2 , —(CH 2 ) 2 COOH, —CH 2 -phenyl, CH 2 -indolyl or CH 2 -imidazolyl; or R b and R 3 , together with the atoms to which they are attached form pyrrolidine ring.
12 . The method of claim 9 , wherein,
R 1 represents hydrogen, —CH 2 —COOH, —CH 2 —CONH 2 , —CH(CH 3 )—CH 2 —CH 3 , —(CH 2 ) 2 CONH 2 , —(CH 2 ) 2 COOH, —(CH 2 ) 3 NHC(═NH)NH 2 , —(CH 2 ) 4 NH 2 , —CH 2 -indolyl, —CH 2 -imidazolyl or —CH 2 -phenyl;
R b is hydrogen; and
R 3 represents hydrogen, —CH 2 —COOH, —CH 2 —CH(CH 3 ) 2 , —CH(CH 3 )—CH 2 —CH 3 , —(CH 2 ) 4 NH 2 , —(CH 2 ) 2 CONH 2 , —(CH 2 ) 2 COOH, —CH 2 -phenyl, CH 2 -imidazolyl or CH 2 -imidazolyl; or R b and R 3 , together with the atoms to which they are attached form pyrrolidine ring.
13 . The method of claim 1 , wherein the compound is represented by compound of formula (IC):
or a pharmaceutically acceptable salt or an amide or an ester, or a stereoisomer thereof; wherein,
R a is hydrogen; R 1 represents-(CH 2 ) 2 COOH, —(CH 2 ) 2 CONH 2 , —(CH 2 ) 3 NHC(═NH)NH 2 , or (CH 2 ) 4 NH 2 ; or R a and R 1 , together with the atoms to which they are attached form pyrrolidine ring; and
R b is hydrogen; R 3 represents hydrogen, —CH 2 -phenyl, —(CH 2 ) 2 CONH 2 , or —(CH 2 ) 2 COOH; or R b and R 3 , together with the atoms to which they are attached form pyrrolidine ring.
14 . The method of claim 1 , wherein the compound is represented by compound of formula (ID):
or a pharmaceutically acceptable salt or an amide or an ester, or a stereoisomer thereof; wherein,
R a is as defined in claim 1 ;
R 1 represents —(CH 2 ) 3 NHC(═NH)NH 2 , —(CH 2 ) 4 NH 2 , or —CH 2 CONH 2 ; and
R b is hydrogen; R 3 represents hydrogen, —(CH 2 ) 3 NHC(═NH)NH 2 , or —(CH 2 ) 4 NH 2 ; or R b and R 3 , together with the atoms to which they are attached form pyrrolidine ring.
15 . The method of claim 1 , wherein the compound is represented by compound of formula (IE):
or a pharmaceutically acceptable salt or an amide or an ester, or a stereoisomer thereof; wherein,
R b is as defined in claim 1 ;
R 2 represents hydrogen, —CH 2 —OH, —(CH 2 ) 2 COOH, —(CH 2 ) 3 NHC(═NH)NH 2 , —CH 2 -phenyl or —CH 2 -indolyl; and
R 3 represents hydrogen, —CH 2 —COOH, —(CH 2 ) 2 COOH, —CH 2 —CH(CH 3 ) 2 , —CH(CH 3 )—CH 2 —CH 3 , —(CH 2 ) 4 NH 2 , —CH 2 -phenyl, —CH 2 -indolyl, or —CH 2 -imidazolyl or R b and R 3 , together with the atoms to which they are attached form pyrrolidine ring.
16 . The method of claim 1 , wherein the compound is represented by compound of formula (IF):
or a pharmaceutically acceptable salt or an amide or an ester, or a stereoisomer thereof; wherein,
R b is as defined in claim 1 ;
R 2 represents hydrogen, —CH 2 -phenyl, —(CH 2 ) 3 NHC(═NH)NH 2 , or —(CH 2 ) 2 COOH;
R 3 represents-CH 2 -phenyl, —(CH 2 ) 2 CONH 2 , —(CH 2 ) 2 COOH, or —(CH 2 ) 4 NH 2 .
17 . The method of claim 1 , wherein the compound is selected from the group consisting of:
Compound
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
or a pharmaceutically acceptable salt or an amide or an ester, or a stereoisomer thereof.
18 . The method of claim 1 , wherein the cancer cell is a cell from melanoma, renal cancer, prostate cancer, breast cancer, colon cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumours of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), non-small cell lung cancer (NSCLC), primary CNS lymphoma, tumour angiogenesis, spinal axis tumour, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, B-cell lymphomas, multiple myeloma, or environmentally induced cancers including those induced by asbestos (e.g., mesothelioma), or combinations of said cancers.
19 . A method for treating or delaying progression of diseases or disorders mediated by CD47 in an individual, the method comprising administering to said individual an effective amount of a compound of formula (I):
or a pharmaceutically acceptable salt or an amide or an ester, or a stereoisomer thereof;
wherein,
R a is hydrogen or acyl; and R 1 represents hydrogen, —(CH 2 ) 2 CONH 2 , —(CH 2 ) 2 COOH, —CH 2 COOH, —(CH 2 ) 3 NHC(═NH)NH 2 , —(CH 2 ) 4 NH 2 , —CH 2 CONH 2 , —CH(CH 3 )—CH 2 —CH 3 , —CH 2 -aryl, or —CH 2 -heteroaryl; wherein the said aryl and heteroaryl are unsubstituted; or R a and R 1 together with the atoms to which they are attached form pyrrolidine ring optionally substituted with oxo group;
R 2 represents hydrogen, —CH 2 —OH, —(CH 2 ) 3 NHC(═NH)NH 2 , —(CH 2 ) 2 CONH 2 , —(CH 2 ) 2 COOH, —CH 2 -aryl, or —CH 2 -heteroaryl; wherein the said aryl and heteroaryl are unsubstituted;
R b is hydrogen; and R 3 represents hydrogen, —CH 2 -aryl, —(CH 2 ) 3 NHC(═NH)NH 2 , —CH 2 COOH, —CH(CH 3 )—CH 2 —CH 3 , —CH 2 —CH(CH 3 ) 2 , —(CH 2 ) 2 CONH 2 , —(CH 2 ) 2 COOH, —(CH 2 ) 4 NH 2 or —CH 2 -heteroaryl; wherein the said aryl and heteroaryl are unsubstituted; or R b and R 3 , together with the atoms to which they are attached form pyrrolidine ring.
20 . The method of claim 19 , wherein the disease or disorder mediated by CD47 is melanoma, renal cancer, prostate cancer, breast cancer, colon cancer and lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumours of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), non-small cell lung cancer (NSCLC), primary CNS lymphoma, tumour angiogenesis, spinal axis tumour, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, B-cell lymphomas, multiple myeloma, or environmentally induced cancers including those induced by asbestos or combinations of said cancers; or bacterial, viral and fungal infections that are HIV, Influenza, Herpes, Giardia , Malaria, Leishmania , a pathogenic infection by the virus Hepatitis A, B, or C, herpes virus, adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus, pathogenic infection by the bacteria chlamydia , rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, E. coli, legionella , diphtheria, salmonella , bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria, pathogenic infection by the fungi Candida, Cryptococcus neoformans, Aspergillus , Genus Mucorales, Sporothrix schenckii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum , and pathogenic infection by the parasites Entamoeba histolytica, Balantidium coli , Naegleria fowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, or Nippostrongylus brasiliensis ; or atherosclerosis or multiple sclerosis.